Angiotensin II (AII) is a potent vasoconstrictor. Its generation in the renin-angiotensin cascade results from the enzymatic action of renin on a blood plasma .alpha.2-globulin, angiotensinogen, to produce angiotensin I (AI). AI is then converted by angiotensin converting enzyme (ACE) to the octapeptide hormone AII. AII has been implicated as a causitive agent in hypertension. Therefore, ACE inhibitiors, which inhibit the production of AII via angiotensin converting enzyme, and AII receptor antagonists, which inhibit the function of AII, no matter the pathway of biosynthesis, are useful in the treatment of hypertension. The efficacy of these compounds in the treatment of heart failure is also being studied.
Pals, et al., Circulation Research, 29, 673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an octapeptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and subsequently "saralasin," was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AII. Captopril and enalapril are commercially available ACE inhibitors (ACEI's). Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with ACEI's. But when a diuretic such as furosemide or hydrochlorothiazide is given together with an ACEI, the blood pressure of most hypertensive patients is effectively normalized. Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renin-dependent state. Although AII antagonist compounds act by a different mechanism, i.e., by blocking the AII receptor rather than by inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the renin-angiotensin cascade. A combination of the ACEI enalapril maleate and the diruetic hydrochlorothiazide is commercially available under the trademark Vaseretic.RTM. from Merck & Co. Publications which relate to the use of diuretics with ACEI's to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W. B., Pharmacol. Rev., 31:81 (1981) and Weinberger, M. H., Medical Clinics N. America, 71:979 (1987). Diuretics have also been administered in combination with saralasin to enhance the antihypertensive effect.
Losartan potassium (losartan) represents the first antihypertensive in the class of AII receptor antagonists which is disclosed in a U.S. Pat. No. 5,138,069 issued on Aug. 11, 1992, and which is assigned to E. I. du Pont de Nemours. Losartan has been demonstrated to be a potent orally active AII antagonist, selective for the AT.sub.1 receptor subtype useful in the treatment of hypertension.
Inhibition of the renin-angiotensin-aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitor and angiotensin II (AII) receptor antagonist therapy has also been shown to prevent and/or ameliorate renal disease of varying etiologies in animal models. Considering the differing pharmacodynamic effects of ACE inhibitors and AII receptor antagonists, i.e., ACE inhibitors (e.g. captopril, enalapril or lisinopril) inhibit the conversion of angiotensin I to angiotensin II and potentiate the effects of the kallikrein-kinin system whereas AT.sub.1 selective AII receptor antagonists (e.g. losartan) selectively inhibit the function of AII at the receptor site, it is reasonable to suggest that an enhanced beneficial effect might be achieved through the coadministration of compounds from these therapeutic classes.
The coadministration of an ACE inihibitor with an AII antagonist for use in the treatment of experimental hypertension and congestive heart failure has been described in patent applications filed by SmithKline Beecham (WO 92/10097) and Pfizer (WO 91/17771). Additionally, a patent application filed by Merck and INSERM (EPO 629408) claims enhanced renal blood flow when treating with the combination. The instant invention discloses the combination of enalapril maleate and losartan potassium for use in the treatment of hypertension and congestive heart failure.